Gold-templated covalent targeting of the CysSec-dyad of thioredoxin reductase 1 in cancer cells

Lukas Skos, Claudia Schmidt, Sophie R. Thomas, Mihyun Park, Verena Geiger, Dominik Wenisch, Riccardo Bonsignore, Giorgia Del Favero, Thomas Mohr, Andrea Bileck, Christopher Gerner, Angela Casini (Korresp. Autor*in), Samuel M. Meier-Menches (Korresp. Autor*in)

Veröffentlichungen: Beitrag in FachzeitschriftArtikelPeer Reviewed

Abstract

Covalent drugs emerged as a promising addition to the arsenal of medicinal chemistry tools. Here, a gold-templated mechanism is exploited to enable the selective covalent targeting of the CysSec-dyad of thioredoxin reductase 1 (TXNRD1) in cancer cells. This two-step mechanism involves reversible coordination of a cyclometalated gold(III) compound, featuring a bidentate CˆN ligand, to thiolates/selenolates, followed by reductive elimination and irreversible covalent cross-coupling reaction of the ligand to these nucleophiles. Following this reactivity, potent inhibition of TXNRD1 activity was shown in vitro, including cancer cell extracts. Selective arylation of the CysSec-dyad in the presence of reducing equivalents was seen in cell-free studies. Chemoproteomic studies showed that the proposed mechanism is selective toward specific protein targets, including TXNRD1. Proteome profiling revealed down-regulation of the detected selenoproteins, except TXNRD1, and induction of the NRF2-KEAP1 pathway. Metal-templated covalent targeting may prove useful to rationally expand the ligandable space of covalent drug discovery.

OriginalspracheEnglisch
Aufsatznummer102072
FachzeitschriftCell Reports Physical Science
Jahrgang5
Ausgabenummer7
DOIs
PublikationsstatusVeröffentlicht - 17 Juli 2024

ÖFOS 2012

  • 106052 Zellbiologie
  • 301904 Krebsforschung

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